Infraestructura de Medicina de Precisión asociada a la Ciencia y la Tecnología
During the last decade, the use of stimulant, antidepressant, antipsychotic and/or anxiolytic drugs for the treatment of mental disorders in the child and adolescent population has increased significantly. However, between 30-50% have a suboptimal response and 20-50% develop severe side effects such as metabolic syndrome, cardiovascular problems and increased suicidal ideation. These have an even greater deleterious effect on the nervous system during early ages, in addition to increasing its mortality. The occurrence of these side effects may differ between boys and girls, a factor that is poorly considered. Most studies on genetic, clinical or environmental factors that contribute to the efficacy or tolerance of drugs have been carried out in the adult population, while information in the child and adolescent population is limited. This lack of information is the main barrier to the personalization of treatment in the child and adolescent population.
OBJECTIVE: Development and implementation of rapid and economical interventions for the personalization of treatment with psychotropic drugs in the child and adolescent population according to age, sex, clinical characteristics and pharmacogenetic profile.
METHODOLOGY: A clinical, genomic, epigenomic and biometric study will be carried out in a cohort of children and adolescents (5-18 years, N=2000) for the development of algorithms for drug and dose selection in this population group. A pilot study will be carried out to evaluate the clinical and economic benefits of the interventions developed.
VIABILITY: In a previous study we showed that pharmacogenetic interventions result in significant clinical improvements (increased efficacy and safety) and economic improvements (reduction of hospital visits and stays) that facilitate their applicability in hospital settings. The protocols developed will be shared with the IMPACT consortium of genomic medicine
The main objective of the proposal is the development and implementation of clinical-pharmacogenetic interventions to improve the efficacy and safety of psychotropic drug treatments in the child and adolescent population.
The secondary objectives are:
A- Identification of demographic, clinical and genetic markers of risk of side effects and efficacy of psychotropic drugs in the child and adolescent population.
B- Determination of the relationship between sex, dose, plasma concentration of drugs and development of side effects during treatment with psychotropic drugs in the child and adolescent population.
C- Investigation of epigenetic alterations associated with the development of side effects and suboptimal response in the child and adolescent population.
D- Development of algorithms based on clinical and genetic information for the selection of appropriate doses and psychotropic drugs in the child and adolescent population.
E- Development of clinical recommendation criteria and intervention protocols for the personalization of treatment in the child and adolescent population easily applicable in hospital settings.
F- Development of applications for the interpretation of results and the preparation of reports in accordance with the criteria and protocols developed and adaptable to hospital electronic systems.
G- Pilot study for the evaluation of the clinical and economic benefits of the protocols developed in hospital clinical practice.
Despite evidence confirming the influence of genetic factors on the efficacy and tolerability of pharmacological treatments, pharmacogenetics is rarely used in clinical practice for the personalization of treatment with psychotropic drugs. The scarce evidence on the clinical and economic benefits of pharmacogenetic interventions, the lack of intervention criteria and protocols, the delay in obtaining information and their high cost are the main barriers to their implementation in psychiatric clinical practice. In addition, there is no information on the specific requirements for adjustments in the child and adolescent population. This project will confirm the clinical and economic benefits of pharmacogenetic interventions, as well as develop fast and inexpensive algorithms and protocols that allow the personalization of treatment in the child and adolescent population.
Personalization of treatment in the child and adolescent population
In recent studies, with the help of a research grant (PERIS oriented project grant, Generalitat de Catalunya), we developed rapid (results in 24-48 hours) and economical methods for the improvement of treatment with antidepressants and antipsychotics using pharmacogenetic information. The methods and protocols developed resulted in a clear improvement in the response in treatment-resistant ASD children and adolescents (publication in preparation). It was observed that all treatment-resistant patients had genetic contraindications to the psychotropic drugs they were receiving, so they needed a change of medication or adjustment of clinical doses. Treatment adjustment according to the pharmacogenetic report resulted in symptom improvement in 90% of cases (CGAS values) and clinical stabilization in 61% of cases (CGAS improvement≥20%).
Clear economic benefits were also observed that will facilitate its viability. The improvement observed in the patients in the study resulted in a reduction in the number of clinical visits and hospital stays. An approximate saving of €1,030 per patient per year was calculated, in addition to the reduction in expenditure on ineffective treatments. As a result of the clinical and economic benefits observed in this study, the HUMT has incorporated the performance of pharmacogenetic tests routinely in the child and adolescent psychiatry service for those children or adolescents who require treatment with antipsychotics or antidepressants.
However, the recommendations used in this preliminary study (dose adjustments and drug selection according to variants in CYP enzymes and serotonin transporter) were based on studies carried out in the adult population and may not be appropriate for the child and adolescent population. Currently, recommendations for dose adjustments according to pharmacogenetic information are based on the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC), developed through data obtained in the adult population. One of the fundamental aspects of this project is the determination of the dose adjustments required in children and adolescents according to their pharmacogenetic profile and sex, which will significantly improve the tolerability of treatments. On the other hand, the pharmacogenetic tests developed in the preliminary study did not include information on stimulant or anxiolytic drugs, which are mostly used in the child and adolescent population, or baseline clinical information. Pharmacogenetic interventions would improve significantly with the incorporation of relevant clinical information and appropriate dose adjustments to the child and adolescent population on the most commonly used drugs, thus being applicable to a large proportion of the pediatric and juvenile population. It is expected that the adjusted selection of psychotropic drugs and doses based on clinical characteristics, age and sex will reduce cardiovascular problems, suicidal ideation and metabolic syndrome, and thus excess mortality in the child and adolescent population.
Viability and Sustainability
The improvement of clinical utility, the adaptability of the methods and protocols designed, their speed and low cost increase acceptance and adoption in hospital environments:
Clinical Utility
The rapid collection of pharmacogenetic information and the consequent elaboration of recommendations in a period of 24-48 hours increases its clinical utility, since the recommendations can be applied before the start of treatment, thus increasing its effectiveness. In addition, the pharmacogenetic information obtained does not change throughout the patient’s life, so it can be included in their medical history for the adjustment of future pharmacological treatments. The information obtained in the protocols developed in this project (i.e. functional variants in CYP enzymes) can be applied to other medical areas (cardiology, oncology, infectious diseases, etc.) thus increasing their productivity.
Adaptability
The genotyping assays used to obtain information on key pharmacogenetic markers are low-cost and easily adaptable to the different technologies existing in clinical laboratories and genotyping platforms.
Validated criteria.
During the project, pharmacogenetic experts and child and adolescent psychiatrists will develop intervention protocols based on clinical, pharmacogenetic and demographic information. These protocols will be shared and discussed with experts from the IMPACT consortium of genomic medicine for validation. As part of this project, a computer application will also be developed for the automatic preparation of clinical-pharmacogenetic reports based on the validated criteria. The validation of criteria and the application of information technology will facilitate the implementation of pharmacogenetic interventions in hospitals and other health centres.
Increased Implementation
Finally, the pilot study will confirm the high clinical utility of clinical-pharmacogenetic protocols for the personalization of treatment with psychotropic drugs in the pediatric and juvenile population. The clear expected clinical and economic benefits will facilitate the acceptance of pharmacogenetic intervention protocols designed by the managing directorates of collaborating hospitals and other health centers. We attach letters of support from directors of areas of the Department of Health of the Generalitat de Catalunya that reflect the interest in the implementation of the protocols and interventions developed in this project in clinical practice.
SOCIAL IMPACT
In our preliminary studies, no rejection of pharmacogenetic testing has been observed. Patients and their families feel empowered and participate in their own treatment, with a high level of satisfaction. Patients and/or their relatives receive information about their pharmacogenetic profile and the implications that this could have on their current or future treatment.
A possible reason for the low implementation of pharmacogenetics in psychiatric clinical practice is the lack of knowledge of its applicability. During the fourth year, informative seminars on the usefulness and application of clinical-pharmacogenetic protocols will be given to health personnel in hospital settings and family associations. The specific results of the project will be disseminated through publications in scientific journals, presentations at conferences and dissemination in the media.